p21 is decreased in polycystic kidney disease and leads to increased epithelial cell cycle progression: roscovitine augments p21 levels.
p21 is decreased in polycystic kidney disease and leads to increased epithelial cell cycle progression: roscovitine augments p21 levels.
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DOI：
10.1186/1471-2369-8-12
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发表时间：
2007-08-22
期刊：
影响因子：
2.3
通讯作者：
Weiss, Robert H
中科院分区：
文献类型：
--
作者：
Park, Jin-Young;Schutzer, William E;Lindsley, Jessie N;Bagby, Susan P;Oyama, Terry T;Anderson, Sharon;Weiss, Robert H
常染色体显性多囊肾病（ADPKD）是一种常见的遗传性疾病，除肾脏替代治疗外，几乎没有其他治疗选择。p21是一种对细胞周期具有多效性作用的细胞周期蛋白激酶抑制剂，在许多情况下起到抑制细胞周期进展和防止细胞凋亡的作用。由于PKD中发生细胞周期阻滞和肾小管上皮细胞凋亡的缺陷，并且根据早期报道，多囊蛋白-1上调p21，细胞周期蛋白依赖性激酶抑制剂roscovitine在小鼠模型中阻滞进展，我们询问（1）p21缺陷是否可能是ADPKD的基础，以及（2）roscovitine对PKD的有益作用机制是否涉及p21。通过免疫印迹和/或荧光化学检测人和动物组织样品以及细胞系中的p21水平。通过PARP切割评估细胞凋亡。通过反义方法减弱肾小管上皮细胞系中的p21表达，并且通过MTT测定评估响应于p21减弱和roscovitine的增殖。我们表明，p21在人类和ADPKD非转基因大鼠模型中减少。此外，肝细胞生长因子，诱导从囊性转化为管状表型，增加p21水平。此外，p21的衰减导致体外细胞周期转运的增强。因此，p21的水平与肾小管上皮细胞增殖呈负相关。Roscovitine已被证明可以阻止PKD小鼠模型的进展，增加p21水平并降低肾小管上皮细胞增殖，对细胞凋亡没有影响。我们的研究的新奇是在人类和大鼠模型中证明了与非囊性肾相比，囊性肾中p21的减少。由于p21介导的上皮细胞增殖和细胞凋亡增强导致囊肿形成增加的潜在发病模型的验证表明了roscovitine在ADPKD中的有益作用的机制，并支持进一步研究p21作为未来治疗的靶点。
Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disease with few treatment options other than renal replacement therapy. p21, a cyclin kinase inhibitor which has pleiotropic effects on the cell cycle, in many cases acts to suppress cell cycle progression and to prevent apoptosis. Because defects in cell cycle arrest and apoptosis of renal tubular epithelial cells occur in PKD, and in light of earlier reports that polycystin-1 upregulates p21 and that the cyclin-dependent kinase inhibitor roscovitine arrests progression in a mouse model, we asked whether (1) p21 deficiency might underlie ADPKD and (2) the mechanism of the salutary roscovitine effect on PKD involves p21. p21 levels in human and animal tissue samples as well as cell lines were examined by immunoblotting and/or immunohistochemisty. Apoptosis was assessed by PARP cleavage. p21 expression was attenuated in a renal tubular epithelial cell line by antisense methods, and proliferation in response to p21 attenuation and to roscovitine was assessed by the MTT assay. We show that p21 is decreased in human as well as a non-transgenic rat model of ADPKD. In addition, hepatocyte growth factor, which induces transition from a cystic to a tubular phenotype, increases p21 levels. Furthermore, attenuation of p21 results in augmentation of cell cycle transit in vitro. Thus, levels of p21 are inversely correlated with renal tubular epithelial cell proliferation. Roscovitine, which has been shown to arrest progression in a murine model of PKD, increases p21 levels and decreases renal tubular epithelial cell proliferation, with no affect on apoptosis. The novelty of our study is the demonstration in vivo in humans and rat models of a decrement of p21 in cystic kidneys as compared to non-cystic kidneys. Validation of a potential pathogenetic model of increased cyst formation due to enhanced epithelial proliferation and apoptosis mediated by p21 suggests a mechanism for the salutary effect of roscovitine in ADPKD and supports further investigation of p21 as a target for future therapy.